No action today, no antibiotics tomorrow…

YOU may have missed the fact that today was a World Health Day devoted to antibiotics; if you hadn’t, then it is, or at least was. In any case, it’s more or less over now and the issue can sink into the din of background noise.

As Frank Swain put it in in his well researched, and typically pithy, Guardian article today:

Health experts have been ringing the alarm over antimicrobial resistance for so long that it seems to have become part of our collective background noise, like the endless rasp of waves on the shore. And like stupid tourists, we sleep in the sun while the tide comes in.

I have to say that a little pithiness is warranted, because if we find ourselves still in this situation in 2021, I’m going to be either, a) A disgruntled cash-strapped senior lecturer / reader / professor with a serious Cassandra complex; b) long since departed from research due to lack of funding; or c) dead, or missing a limb, due to an untreatable bacterial infection, or grieving over the same in a loved one.

I’ve written previously about some of the reasons we don’t have new drugs, and we can keep re-stating these issues til the cows come home, but it doesn’t mean anything will actually change. The broad response of governments following the ReAct meeting in Stockholm last year was more words, then an eerie silence. Similarly, in a meeting of the British Society for Antimicrobial Chemotherapy (BSAC), bylined ‘The Urgent Need’, more words were said amongst people who already familiar with those words, following which there was also been an eerie silence.

There is a lot of pussy-footing around, and needless to say that governments need to put money where their inordinately large mouth is and start paving the way for incentives for drug discovery. In the meanwhile, what can we lowly researchers do? Well, we can actually get heavily involved in drug discovery ourselves, and on this subject I have several of my own pithy points to make:

1. Natural compounds are a way forward. As I have said before what are needed are truly novel chemicals; bat-shit crazy, funky, out of the box new chemicals developed by willing, well-funded and eager researchers. There are drugs out there that are irrational, don’t conform to Lipinski’s rule of five, are probably a little precocious, but amongst them could be gems. Our lab is now actively engaged in this process, and this area will be further aided by metagenomic approaches, which allow us to mine for genes of a far greater number of organisms than we could ever culture in a laboratory. I liken it to Googling for a search term, rather than buying a book and searching that for any given term. It is, however, still worth developing new culture techniques to grow previously unculturable bacteria, because there may be useful chemical products that they produce – perhaps when grown in the presence of its community members – that we can’t really identify via metagenomic approaches. I’ll be writing more about the specifics of these approaches in coming posts.

2. For well over a decade people have lamented that fact that all the antibiotics we have are targeted at a handful of bacterial physiological processes, i.e. interfering with DNA, proteins, a couple of metabolic pathways, or the components of the wall that bacterial cells use to keep their insides from becoming their outsides. Thus, a large number of labs invest much time and effort in identifying new physiological targets for drugs. This is all very well, and very academic, but my retort has always been, ‘What drugs?’ This is the crux of the matter; it’s all very well having new targets, but if you have no drugs, what good is that? What we need are drugs, and what we already have are a set of awesomely good and pretty well characterised targets. So let’s just go fill the arsenal full of drugs that hit those targets we have shall we, because by my clock we’ve got 15 years even if we know the target and find a new drug tomorrow; if you want to add a new target on to that, you may as well add another 5-10 years to that tally.

3. The ‘Analogue Age’, so defined by Prof Tony Coates as the age when the original set of natural compounds were modified slightly (to make an analogue) to overcome bacterial resistance to them, may yet be useful for the refinement of some older antibiotics. Chemical technology has advanced apace, and there may be scope to take very old antibiotics such as colistin, which I’m assuming was one of those drugs Frank referred to as, ‘our most clumsy, brutal antibiotics’, and reduce their toxicity. Likewise, there are moves afoot to consider ways of taking some of the successful anti-MRSA drugs and re-tasking them to Gram-negative bacteria by developing ways to get them past the intrinsic (i.e naturally occurring, rather than acquired) resistance Gram-negatives have to many drugs.

4. The current model for drug discovery is towards drugs that interfere with actively growing bacteria, however, bacteria aren’t always actively growing. I’ve written before about how being in a different growth-phase can render a bacterial cell resistant to antibiotics. This can lead to repeated flare-ups of the infection until, eventually, true genetic resistance evolves that allows the bacteria to survive, and continue growing in the presence of the antibiotic. Thus there is the proposal that as part of enhanced efforts in drug discovery, that a platform for developing drugs at slow- or non-growing bacteria be practised.

4. The most common effect we find when testing a new chemical agent is that it it disrupts the bacterial membrane that envelopes the cell, a very important component of any cell. Whilst this can be a good thing to see in bacteria, such agents often also do the same in human cells. The lesson here is that it’s not hard to find drugs that kill bacteria, the trick is to find drugs that kill bacteria, and not us. Thus, how useful are continued announcements of new drug discoveries where the membrane-damaging activity of the drug against human cells (which, as I say, isn’t good a good thing) has yet to be established? To researchers in the field, unless you’ve demonstrated that your compound isn’t cytotoxic to human cells, irrespective of how awesomely good it is at killing bacteria, perhaps delay the press release? On the flip side, drugs that are no good for our needs, due to their toxicity, can be quite interesting to cancer researchers who may then look to see whether the toxicity is more pronounced on fast-growing cancer cells and thus become viable chemotherapy leads for them.

5. There’s always someone who, at this point, mentions phage-therapy, and how there is a big conspiracy in the west to not work on the technology. Phage therapy is a nice idea in theory, but in practice it has many flaws. The Russians aren’t stupid, if phage therapy could have been made to work effectively, they would have done so; the reason they worked with phage in the first place was because they didn’t have access to antibiotics. The fact that we went with antibiotics, rather than phage, following their discovery is testament to their effectiveness. A few choice anecdotes of successful phage-treatment does not mean it is a wholly viable technology; there has yet to be a full double-blind, placebo controlled clinical trial of systemically delivered phage therapy for the treatment of systemic infection. Phage may, however, have some utility as additives to topical wound dressings, much like silver impregnation is currently employed, and this may improve wound healing.

6. Antimicrobial peptides. Again, nice idea, relatively easy to work with and derivatise. However, much of the utility of antimicrobial peptides is built on the premise that little or no resistance to them has been seen. This simply isn’t true, and given that antimicrobial agents are an important component of our own innate immune system, the idea of genes conferring cross-resistance to our own antimicrobial peptides worries me; this will be the subject of my next post.

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